We discovered a novel gene called Sox18, which plays a critical role on blood vessel development and the formation of the lymphatic vessel network. Sox18 mutations underlie the mouse mutant Ragged (Ra), which is characterized by edema suggesting blood vessel and/or lymphatic dysfunction. Sox18 is also defective in a human vascular/lymphatic disorder, hypotricosis-lymphedema-telangiectasia.
The aim of this project is to clarify the role of Sox18 in the development and function of the vascular and lymphatic system. During blood vessel development, Sox18 appears to play multiple roles including endothelial cell differentiation, arteriovenous specification and vascular integrity. Sox18 is also reactivated during wound healing and tumour angiogenesis; remarkably, suppressing Sox18 function restricts tumour growth.
Sox18 plays a critical role in the embryo as the master switch gene that initiates development of the lymphatic vessel system. Our work has revealed that it performs this function by regulating the lymphatic hallmark gene Prox1. Mice deficient in Sox18 develop no lymphatic vessels. Also, tumours induced in Sox18-deficient mice do not metastasize to the same extent as tumours in normal mice. Therefore, we are now developing chemical modifiers of Sox18 activity that may be useful as drugs to suppress tumour growth and metastasis. .
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François, M, Caprini, A, Hosking, B, Orsenigo, F, Wilhelm, D, Browne, C, Paavonen, K, Karnezis, T, Shayan, R, Downes, M, Davidson, T, Tutt, D, Cheah, KSE, Stacker, SA, Muscat, GEO, Achen, MG, Dejana, E and Koopman, P (2008). SOX18 induces development of the lymphatic vasculature in mice.
Downes, M, Francois, M, Ferguson, C, Parton, RG and Koopman, P (2009). Vascular defects in a mouse model of hypotrichosis-lymphedema-telangiectasia syndrome indicate a role for SOX18 in blood vessel maturation.
Francois, M, Koopman, P and Beltrame, M (2009). SoxF genes: Key players in the development of the cardio-vascular system.
Hosking, B, Francois, M, Wilhelm, D, Orsenigo, F, Caprini, A, Svingen, T, Tutt, D, Davidson, T, Browne, C, Dejana, E and Koopman, P (2009). Sox7 and Sox17 are strain-specific modifiers of the lymphangiogenic defects caused by Sox18 dysfunction in mice.